Separation of graft-versus-host disease from graft-versus-leukemia responses by targeting CC-chemokine receptor 7 on donor T cells

JM Coghill, MJ Carlson… - Blood, The Journal …, 2010 - ashpublications.org
JM Coghill, MJ Carlson, A Panoskaltsis-Mortari, ML West, JE Burgents, BR Blazar
Blood, The Journal of the American Society of Hematology, 2010ashpublications.org
Abstract CC-chemokine receptor 7 (CCR7) is expressed on the surface of naive T cells, and
plays a critical role in their movement into secondary lymphoid tissue. Here, we show that
murine T cells lacking CCR7 (CCR7−/−) generate attenuated graft-versus-host disease
(GVHD) responses compared with wild-type (WT) cells, with the difference varying inversely
with the degree of major histocompatibility complex (MHC) disparity between the donor and
recipient. CCR7−/− T cells exhibited an impaired ability to traffic to recipient lymph nodes …
Abstract
CC-chemokine receptor 7 (CCR7) is expressed on the surface of naive T cells, and plays a critical role in their movement into secondary lymphoid tissue. Here, we show that murine T cells lacking CCR7 (CCR7−/−) generate attenuated graft-versus-host disease (GVHD) responses compared with wild-type (WT) cells, with the difference varying inversely with the degree of major histocompatibility complex (MHC) disparity between the donor and recipient. CCR7−/− T cells exhibited an impaired ability to traffic to recipient lymph nodes, with an increased capacity to home to the spleen. CCR7−/− T cells, however, demonstrated a reduced ability to undergo in vivo expansion in the spleen due to impaired interactions with splenic antigen-presenting cells. On a cellular level, CCR7−/− T cells were functionally competent, demonstrating a normal in vitro proliferative capacity and a preserved ability to produce inflammatory cytokines. Importantly, CCR7−/− T cells were capable of generating robust graft-versus-leukemia (GVL) responses in vivo, as well as complete donor T-cell reconstitution. CCR7−/− regulatory T cells were able to protect against lethal GVHD when administered before WT conventional T cells. Our data suggest that CCR7 inhibition in the early posttransplantation period may represent a feasible new therapeutic approach for acute GVHD attenuation without compromising GVL responses.
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